{"doi":"10.1083/jcb.202006021","title":"Tyrosine phosphorylation of S1PR1 leads to chaperone BiP-mediated import to the endoplasmic reticulum","abstract":"Cell surface G protein-coupled receptors (GPCRs), upon agonist binding, undergo serine-threonine phosphorylation, leading to either receptor recycling or degradation. Here, we show a new fate of GPCRs, exemplified by ER retention of sphingosine-1-phosphate receptor 1 (S1PR1). We show that S1P phosphorylates S1PR1 on tyrosine residue Y143, which is associated with recruitment of activated BiP from the ER into the cytosol. BiP then interacts with endocytosed Y143-S1PR1 and delivers it into the ER. In contrast to WT-S1PR1, which is recycled and stabilizes the endothelial barrier, phosphomimicking S1PR1 (Y143D-S1PR1) is retained by BiP in the ER and increases cytosolic Ca2+ and disrupts barrier function. Intriguingly, a proinflammatory, but non-GPCR agonist, TNF-α, also triggered barrier-disruptive signaling by promoting S1PR1 phosphorylation on Y143 and its import into ER via BiP. BiP depletion restored Y143D-S1PR1 expression on the endothelial cell surface and rescued canonical receptor functions. Findings identify Y143-phosphorylated S1PR1 as a potential target for prevention of endothelial barrier breakdown under inflammatory conditions.","journal":"The Journal of Cell Biology","year":2021,"id":199469,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":775968,"name":"Md Ruhul Amin","orcid":"0000-0002-5795-074X","position":1,"is_corresponding":false},{"id":562309,"name":"Vijay Avin Balaji Ragunathrao","orcid":"0000-0001-6032-4048","position":2,"is_corresponding":false},{"id":325619,"name":"Jacob Matsche","orcid":"0000-0003-4743-0297","position":3,"is_corresponding":false},{"id":325623,"name":"Andrei V. Karginov","orcid":"0000-0003-2370-6383","position":4,"is_corresponding":false},{"id":461401,"name":"Richard D. Minshall","orcid":"0000-0003-3164-475X","position":5,"is_corresponding":false},{"id":289760,"name":"Gary Mo","orcid":"0000-0002-3191-2155","position":6,"is_corresponding":false},{"id":533265,"name":"Yulia Komarova","orcid":"0000-0002-3526-6082","position":7,"is_corresponding":false},{"id":241668,"name":"Dolly Mehta","orcid":"0000-0003-0945-9304","position":8,"is_corresponding":false},{"id":486240,"name":"Mumtaz Anwar","orcid":"0000-0001-5711-7312","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-18T23:50:40.558460Z","pmid":"34652421","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}